Abstract CT544: Multi-omics analysis uncovers prognostic biomarkers and tumor ecosystem dynamics during toripalimab combined with nab-paclitaxel and s-1 as neoadjuvant therapy for esophageal squamous carcinoma: A single-center, open-label, single-arm phase 2 trial
Authors: Guoqing Zhang, Jing Yuan, Chaohu Pan, Qing Xu, Xiaoli Cui, Jing Zhang, Minglu Liu, Zhigang Song, Liangliang Wu, Dongfang Wu, Bo Yang, Haitao Luo, Yi Hu, Shunchang Jiao
Journal: Cancer Research (2022)

Abstract Background: Immune checkpoint inhibitor (ICI) combined with chemotherapy as a neoadjuvant therapy has been applied to the treatment of ESCC. However, the optimal regimen needs to be further explored, and the mechanisms by which the ICI combined with chemotherapy modulates the evolution of ESCC are unknown. Methods: In this single-arm phase 2 trial, patients received nab-paclitaxel 260 mg/m2 for 2 cycles and oral S-1 (d1-14, bid) for two weeks, combined with 240 mg intravenous toripalimab for 2 cycles before surgery. The primary outcome was the major pathological response (MPR). Biopsies and plasma before and after neoadjuvant therapy were analyzed for whole-exome sequencing, transcriptome sequencing, PD-L1 expression and 92 proteins using proximity extension assay technology. Results: After neoadjuvant therapy, 26 patients (48.15%) achieved MPR, 16 (29.63%) achieved pCR. 18.3% of the patients experienced grade ≥3 AEs. Compared to patients PD-L1-low, patients with PD-L1-high had a significant higher ratio of PR. During therapy, TMB and TNB were significantly decreased in PR patients, and the ratio of gained and increased clones were significantly lower in MPR patients than nonMPR patients, while the lost and decreased clones were significantly higher in MPR patients than nonMPR patients. Transcriptome analyses before and during therapy revealed CD8 and CD4 T cells were increased in all patients, however, the exhausted cells, nTreg and iTreg were significantly increased in nonMPR patients. Proteins analyses revealed the levels of TRAIL and MUC16 were significantly increased in MPR and PR patients, respectively, while the levels of IFN-γ and IL18 were significantly decreased in MPR and PR patients, respectively. And the expression of ADA, ARG1, CD83, TNFRSF4 and VEGFR2 in plasma were found to be related with serious adverse events. Conclusion: In this study, neoadjuvant therapy with toripalimab, nab-paclitaxel and S-1 was well tolerated and showed promising antitumor activity in patients with resectable ESCC, and the changes of genomic, transcriptome, PD-L1 expression and proteins in plasma were comprehensively analyzed and correlated with clinical outcomes, which provided insight into the mechanism of action of Toripalimab combined with nab-Paclitaxel and S-1 in ESCC patients. Citation Format: Guoqing Zhang, Jing Yuan, Chaohu Pan, Qing Xu, Xiaoli Cui, Jing Zhang, Minglu Liu, Zhigang Song, Liangliang Wu, Dongfang Wu, Bo Yang, Haitao Luo, Yi Hu, Shunchang Jiao. Multi-omics analysis uncovers prognostic biomarkers and tumor ecosystem dynamics during toripalimab combined with nab-paclitaxel and s-1 as neoadjuvant therapy for esophageal squamous carcinoma: A single-center, open-label, single-arm phase 2 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT544.